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Article: Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in hela cancer cells

TitleTimosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in hela cancer cells
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2008, v. 68 n. 24, p. 10229-10237 How to Cite?
AbstractTimosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, exhibits potent cytotoxicity and has the potential to be developed as an anticancer agent. Here, we provide evidence that TAIII induces autophagy in HeLa cells followed by apoptotic cell death. TAIII-induced autophagy was morphologically characterized by the formation of membrane-bound autophagic vacuoles recognizable at the ultrastructural level. TAIII-treated cells expressing green fluorescent protein (GFP)-labeled microtubule-associated protein 1 light chain 3 (LC3) displayed punctate fluorescence indicative of LC3 recruitment to the autophagosome. This was associated with the conversion of LC3-I (the cytosolic form) into LC3-II (the lipidated form located on the autophagosome membrane). TAIII treatment also induced mitochondrial dysfunction involving overproduction of reactive oxygen species and reduction of mitochondrial membrane potential accompanied by induction of mitochondrial permeability transition. Prolonged exposure to TAIII resulted in cytochrome c release and caspase-3 activation, events that signified the onset of apoptotic cell death. TAIII-induced autophagy preceded apoptosis, as evidenced by early autophagic vacuole formation, GFP-LC3 translocation, and LC3-II increase in the absence of caspase-3 cleavage. Notably, TAIII-mediated apoptotic cell death was potentiated by treatment with autophagy inhibitor 3-methyladenine or small interfering RNA against the autophagic gene beclin 1. These findings suggest that TAIII-elicited autophagic response plays a protective role that impedes the eventual cell death. In terms of structure-activity relationship, the sugar chain in TAIII is indispensable to the drug action, as the sugar-lacking aglycone sarsasapogenin did not induce autophagy and exhibited weaker cytotoxicity. ©2008 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/168350
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSy, LKen_US
dc.contributor.authorYan, SCen_US
dc.contributor.authorLok, CNen_US
dc.contributor.authorMan, RYKen_US
dc.contributor.authorChe, CMen_US
dc.date.accessioned2012-10-08T03:17:53Z-
dc.date.available2012-10-08T03:17:53Z-
dc.date.issued2008en_US
dc.identifier.citationCancer Research, 2008, v. 68 n. 24, p. 10229-10237en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/168350-
dc.description.abstractTimosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, exhibits potent cytotoxicity and has the potential to be developed as an anticancer agent. Here, we provide evidence that TAIII induces autophagy in HeLa cells followed by apoptotic cell death. TAIII-induced autophagy was morphologically characterized by the formation of membrane-bound autophagic vacuoles recognizable at the ultrastructural level. TAIII-treated cells expressing green fluorescent protein (GFP)-labeled microtubule-associated protein 1 light chain 3 (LC3) displayed punctate fluorescence indicative of LC3 recruitment to the autophagosome. This was associated with the conversion of LC3-I (the cytosolic form) into LC3-II (the lipidated form located on the autophagosome membrane). TAIII treatment also induced mitochondrial dysfunction involving overproduction of reactive oxygen species and reduction of mitochondrial membrane potential accompanied by induction of mitochondrial permeability transition. Prolonged exposure to TAIII resulted in cytochrome c release and caspase-3 activation, events that signified the onset of apoptotic cell death. TAIII-induced autophagy preceded apoptosis, as evidenced by early autophagic vacuole formation, GFP-LC3 translocation, and LC3-II increase in the absence of caspase-3 cleavage. Notably, TAIII-mediated apoptotic cell death was potentiated by treatment with autophagy inhibitor 3-methyladenine or small interfering RNA against the autophagic gene beclin 1. These findings suggest that TAIII-elicited autophagic response plays a protective role that impedes the eventual cell death. In terms of structure-activity relationship, the sugar chain in TAIII is indispensable to the drug action, as the sugar-lacking aglycone sarsasapogenin did not induce autophagy and exhibited weaker cytotoxicity. ©2008 American Association for Cancer Research.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshAnemarrhena - Chemistryen_US
dc.subject.meshAntineoplastic Agents, Phytogenic - Pharmacologyen_US
dc.subject.meshApoptosis - Drug Effects - Physiologyen_US
dc.subject.meshApoptosis Regulatory Proteins - Geneticsen_US
dc.subject.meshCaspase 3 - Metabolismen_US
dc.subject.meshCatalase - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCyclosporine - Pharmacologyen_US
dc.subject.meshCytochromes C - Metabolismen_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshMembrane Potential, Mitochondrial - Drug Effectsen_US
dc.subject.meshMembrane Proteins - Geneticsen_US
dc.subject.meshMitochondria - Drug Effects - Metabolism - Physiologyen_US
dc.subject.meshOxidative Stress - Drug Effectsen_US
dc.subject.meshRna, Small Interfering - Geneticsen_US
dc.subject.meshReactive Oxygen Species - Metabolismen_US
dc.subject.meshSaponins - Pharmacologyen_US
dc.subject.meshSuperoxide Dismutase - Metabolismen_US
dc.titleTimosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in hela cancer cellsen_US
dc.typeArticleen_US
dc.identifier.emailSy, LK:sylk@hkucc.hku.hken_US
dc.identifier.emailLok, CN:cnlok@hku.hken_US
dc.identifier.emailMan, RYK:rykman@hkucc.hku.hken_US
dc.identifier.emailChe, CM:cmche@hku.hken_US
dc.identifier.authoritySy, LK=rp00784en_US
dc.identifier.authorityLok, CN=rp00752en_US
dc.identifier.authorityMan, RYK=rp00236en_US
dc.identifier.authorityChe, CM=rp00670en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-08-1983en_US
dc.identifier.pmid19074891-
dc.identifier.scopuseid_2-s2.0-57749085555en_US
dc.identifier.hkuros155970-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-57749085555&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume68en_US
dc.identifier.issue24en_US
dc.identifier.spage10229en_US
dc.identifier.epage10237en_US
dc.identifier.isiWOS:000261866800029-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridSy, LK=35874602700en_US
dc.identifier.scopusauthoridYan, SC=7401744858en_US
dc.identifier.scopusauthoridLok, CN=7006410829en_US
dc.identifier.scopusauthoridMan, RYK=7004986435en_US
dc.identifier.scopusauthoridChe, CM=7102442791en_US

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